In collaboration with several Principal Investigators at the CCR/NCI, in silico screening of large small-molecule databases are being conducted for a number of molecular targets relevant for cancer. We are using the (http://ccr.cancer.gov/staff/staff.asp?profileid=6282) CADD Group's resources, including our screening (http://ccrintra.cancer.gov/cms/annual_reports/printer_friendly_report.asp?ProjID=3876) databases to generate lists of compounds to be purchased from (http://www.chemnavigator.com/nih.asp) commercial suppliers , with the goal of obtaining novel lead compounds in in vitro and/or cell-based assays. Currently, we are predominantly working on the targets Akt (PH domain), in collaboration with Phillip Dennis, Cancer Therapeutics Branch, CCR, NCI; c-Met, in collaboration with Donald Bottaro, Urologic Oncology Branch, CCR, NCI, and Terrence R. Burke, Jr., Laboratory of Medicinal Chemistry, CCR, NCI; HSP90, in collaboration with Len Neckers, Cell & Cancer Biology Branch, CCR, NCI; polo-Box domain of polo-like kinase 1, in collaboration with Kyung S. Lee, Laboratory of Metabolism, CCR, NCI; Grb2 SH2 domain, in collaboration with Terrence R. Burke, Jr., Laboratory of Medicinal Chemistry, CCR, NCI; PKC, in collaboration with Peter Blumberg, Laboratory of Cancer Biology and Genetics, CCR, NCI, and Victor E. Marquez, Laboratory of Medicinal Chemistry, CCR, NCI; tyrosyl-DNA phosphodiesterase (Tdp1), in collaboration with Yves Pommier, Laboratory of Molecular Pharmacology, CCR, NCI; and imidazoacridone DNA intercalators, in collaboration with Sergei Tarasov and Christopher Micheijda, Structural Biophysics Laboratory, CCR, NCI. Targets for which work has been completed in 2006 include lecithin retinol acyltransferase (LRAT) and related proteins, in collaboration with Denise Simmons and Luigi DeLuca, Laboratory of Cellular Carcinogenesis and Tumor Promotion, CCR, NCI; and ABCG2, in collaboration with Heidi Bokesch, Molecular Targets Development Program, CCR, NCI. For both Akt and c-Met, initial hit sets have been generated, screening samples purchased, and these samples assayed by our collaborators. First results show inhibitory activity for a number of samples in either assay.